A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations

Nathalie Busschaert, Seong Hyun Park, Kyung Hwa Baek, Yoon Pyo Choi, Jinhong Park, Ethan N.W. Howe, Jennifer R. Hiscock, Louise E. Karagiannidis, Igor Marques, Vítor Félix, Wan Namkung, Jonathan L. Sessler, Philip A. Gale, Injae Shin

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Abstract

Perturbations in cellular chloride concentrations can affect cellular pH and autophagy and lead to the onset of apoptosis. With this in mind, synthetic ion transporters have been used to disturb cellular ion homeostasis and thereby induce cell death; however, it is not clear whether synthetic ion transporters can also be used to disrupt autophagy. Here, we show that squaramide-based ion transporters enhance the transport of chloride anions in liposomal models and promote sodium chloride influx into the cytosol. Liposomal and cellular transport activity of the squaramides is shown to correlate with cell death activity, which is attributed to caspase-dependent apoptosis. One ion transporter was also shown to cause additional changes in lysosomal pH, which leads to impairment of lysosomal enzyme activity and disruption of autophagic processes. This disruption is independent of the initiation of apoptosis by the ion transporter. This study provides the first experimental evidence that synthetic ion transporters can disrupt both autophagy and induce apoptosis.

Original languageEnglish
Pages (from-to)667-675
Number of pages9
JournalNature chemistry
Volume9
Issue number7
DOIs
Publication statusPublished - 2017 Jul 1

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All Science Journal Classification (ASJC) codes

  • Chemistry(all)
  • Chemical Engineering(all)

Cite this

Busschaert, N., Park, S. H., Baek, K. H., Choi, Y. P., Park, J., Howe, E. N. W., Hiscock, J. R., Karagiannidis, L. E., Marques, I., Félix, V., Namkung, W., Sessler, J. L., Gale, P. A., & Shin, I. (2017). A synthetic ion transporter that disrupts autophagy and induces apoptosis by perturbing cellular chloride concentrations. Nature chemistry, 9(7), 667-675. https://doi.org/10.1038/nchem.2706